Application of Immunotherapy in Bladder Cancer Treatment

Introduction:

The parts of the human urinary system are the kidneys, urethra, urinary bladder, and ureter. All these organs function together for the production of urine, storage of urine, and excretion of urine. The urinary bladder is a pear-shaped hollow organ that is situated in front of the pelvic cavity. The usual volume of the urinary bladder is 400 to 600 millimeters. This muscular organ serves as a storage site for urine and also helps in the urination process. Urinary bladder cancer is one of the most common complications of the urinary tract. Nowadays, immunotherapy is considered a promising option for treating bladder cancer.

What Is Bladder Cancer?

Bladder cancer is the most common type of cancer of the urinary tract. It is the fourth most common cancer among men and the seventh most commonest cancer in the world. It is the sixth most common among men in the United States. Genetic factors are one of the predisposing causes of bladder cancer. Patients suffering from bladder cancer often have a family history. Genetic mutation of genes HRAS, RB1, NAT2, and GSTM1.

The risk factors for bladder cancer are smoking, occupational exposure to the chemicals, carcinogenic chemicals, and schistosomiasis infection (infection caused by parasitic worms). Chemicals like arsenic, cyclophosphamide (a medicine used for the treatment of neoplasms), arylamine dye, and aniline dye are one of the causes. Exposure to substances like petroleum products, rubber, and paint is associated with such types of cancer.

The bladder can be of three types. 90 percent of cases of bladder cancer belong to urethral carcinoma. Other types are adenocarcinoma and squamous cell carcinoma of the urinary bladder. According to the mood of invasion, it can be non-invasive, non-muscle invasive, and muscle-invasive.

The symptoms of bladder cancer are:

• Increased frequency of urination and urination during night times.

• Presence of blood in the urine. Sometimes blood clots are present.

• Pain and burning sensation during urination.

• The increased urge to urinate but no urinary output.

• Unilateral pain in the lower back region or pain in the abdomen.

What Are the Different Treatment Options for Bladder Cancer?

Different treatment options followed for the treatment of bladder cancer are:

1. Surgical removal of cancerous parts is one of the most commonly followed treatment options. The excision of the cancerous part depends upon factors like the cancer site and its involvement. Chemotherapy can be used before surgical removal to shrink the size of the cancerous part. Surgical options like transurethral resection with fulguration (removal of the cancerous part along with burning the cancerous tissues), partial cystectomy (removal of part of the bladder), and radical cystectomy with urinary diversion (removal of the bladder along with lymph node).

2. Radiation therapy uses high-energy sources to kill cancer cells. Most of the time, external beam therapy is used for treating bladder cancer.

3. Chemotherapy is used to restrict the growth of cancer cells. Most of the time, it is used prior to the surgical treatment options. It can also be used after surgical treatment. The systemic chemotherapeutic agents are injected via a vein. Another method of chemotherapeutic treatment is intravesical chemotherapy. In this option, drugs are inserted into the urethra via a tube.

What Is Immunotherapy?

The microenvironment of the cancer cells is comprised of different cells types like precursor cells, pericytes, myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs), tumor-associated macrophages, tumor-associated neutrophils, regulatory

T cells (Tregs), and tumor-associated dendritic cells. These cells can suppress immune cell expression and can escape immune surveillance mechanisms. This is essential for the progression of cancer cells. The mechanisms behind these processes are:

• Resistance of the tumor cells due to deficient expression of the major histocompatibility complex (MHC).

• Release of the cytokines, which are immunosuppressive.

• Death of the T lymphocytes.

Immunotherapy is a treatment method in which the immunity system of the body is activated and is used to kill cancer cells. Dr. William B. Coley first proposed the use of such therapy in cancer treatment.

Immunotherapy for cancer treatment can be categorized into three types. These are:

1. Immune Checkpoint Inhibitors: PD-L1 protein and the PD-1 receptor prevent the immune system from interacting with the cancer cells. These types of drugs prevent this interaction and let the immune cells attack the cancer cells. Drugs belonging to this category are Atezolizumab, Atezolizumab, and Pembrolizumab.

2. Cancer Vaccines: These are not cancer-preventing vaccines. But vaccines target the proteins present in the cancer cells and make them susceptible to the immune system. Vaccines like Bacillus Calmette–Guerin can be used for treating bladder cancer.

3. Adoptive T Cell Therapy: The death of the T cell is one of the main features of lung cancer. In these conditions functionality of the T lymphocytes is increased through laboratory techniques, and they are administered into the body to kill cancer cells.

4. Anti-CTLA-4 Antibodies: Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a surface molecule expressed by activated T lymphocytes. This protein binds to the B- lymphocytes, dendritic cells, and macrophages. As these proteins inhibit the functioning of T lymphocytes, the negative regulation of such proteins boosts immunity. Ipilimumab is a drug that belongs to this group.

What Are the Different Immunotherapeutic Drugs?

Different drugs used for the treatment of bladder cancer are:

1. Bacillus Calmette–Guerin (BCG): Intravesical therapy with BCG is a standard approach for treating non-muscle invasive bladder cancer. It is also used for treating in situ cancer causes, papillary tumors, and invasive plaque-propitious tumors. The drugs reduce the chances of recurrence after transurethral bladder resection. These vaccines elicit an immune response and activation of CD4+ and CD8+ lymphocytes.

2. Atezolizumab: It is a monoclonal antibody of IgG1 that acts as a PD-1/PD-L1 inhibitor. It inhibits the interaction between PD-1 and B7.1 receptors and restricts the growth of locally advanced or metastatic urothelial bladder cancer. It is also used as a second line of treatment for advanced cases of bladder cancer.

3. Pembrolizumab: It is an IgG4/kappa monoclonal antibody. It can be used for the second line of treatment in cases of platinum-refractory urothelial carcinoma. This drug is popular for its low adverse effects and high safety profile.

4. Avelumab: It is an anti-PD-L1 monoclonal antibody. This drug received its approval in 2017 from FDA (Food and Drug Administration). This is useful for treating metastatic bladder carcinoma.

5. Ipilimumab: this drug is mainly used for combination therapy. This can also be used in cases of advanced renal cell carcinoma.

Conclusion:

Bladder cancer is one of the most common cancers of the urinary tract. Apart from genetic factors, factors like smoking and alcoholism are also associated with increased incidence of bladder cancer. Surgical resection, radiotherapy, and chemotherapy are conventional methods of treatment in such cases. Immunotherapy can be considered as the first line of treatment in early cases of bladder cancer. Also, this is used as adjuvant therapy and part of the combination treatment.